Wine has been shown to have intrinsic medicinal properties. Polyphenols and moderate wine consumption have been suggested as preventive medicine, but the cellular mechanisms are unclear. Knowing that heme oxygenase (HO) plays various roles in oxidative stress and ischemia, we have tested the hypothesis that HO could participate in polyphenol neuroprotective function. HO enzyme cleaves heme (pro-oxidant) to form biliverdin/bilirubin, carbon monoxide, and iron. Using primary neuronal cultures, our results reveal that resveratrol is one of the most potent inducers of HO1 within neurons and that pre-treatment is sufficient to provide neuroprotection. This work, combined with the finding that ethanol in combination with resveratrol or quercetin would have synergistic effects, allows us to propose that some of the attributed neuroprotective effects of red wine could be mediated through induction of HO1 and the associated beneficial actions of heme degradation and its bioactive metabolites. We will determine whether pre-treatment with resveratrol or quercetin by themselves can affect blood flow and whether the respective polyphenols in combination with alcohol have synergistic effects in mice. If so, then HOI-t- mice will be tested. Second, we will determine whether these treatments can reduce excitotoxicity in the striatum following stereotaxic injection of NMDA. We will test whether polyphenols and alcohol induce changes in HO1 expression that result in changes in cell survival from mouse neuronal cultures against NMDA-induced toxicity. Once a beneficial effect is established, in order to address possible cellular mechanisms of action, primary cultured neurons derived from HOI-/- mice will be tested in parallel with the WT cultures. In addition, use of HO inhibitor will be added to further test the specificity of this effect. These results will indicate for the first time whether preconditioning is sufficient to afford neuroprotection and whether the effect is modulated by HOI. We will test this new hypothesis that some of the beneficial effects attributed to red wine, such as increased cerebral blood flow and reduced ischemic damage, could be attributed to HO1 induction itself and its biological actions. The data will suggest new pathways to explain this neuroprotective effect and how it could provide brain's resistance in acute and chronic neurodegenerative disorders.